Crystalline silica is well known to induce chronic lung inflammation that can progress to fibrosis, i.e. silicosis. Despite existing standards, silicosis remains a prevalent health problem in the United States and throughout the world. Because it is a known causative agent of lung fibrosis, it is often used to study mechanisms of fibrogenesis under controlled conditions in animal models. While much has been learned, there is still insufficient information on the molecular and cellular mechanisms leading to fibrosis to develop effective therapeutic approaches. It is generally accepted that alveolar macrophages are the initial cellular targets following silica inhalation and that macrophages are involved in the initiation of inflammatory signals and that mostly likely lymphocytes are also involved, since Th1- and Th2- associated cytokines have been repeatedly implicated in the process of fibrosis. Based on recent data from our laboratory, as well as others, implicating activated lung macrophages (aMQ) and NK lymphocytes as being sufficient to set off the inflammatory cycle leading to fibrosis we propose to test the central hypothesis that aMQ with NK lymphocytes constitute steps in the development of chronic inflammation progressing to silicosis. We will use the following three aims to test this hypothesis: Specific Aim 1: Characterize the silica-exposed alveolar macrophages that traffic to the interstitial spaces, acquire an immunostimulatory phenotype, and play an integral role in the generation of the aMQ. Specific Aim 2: Demonstrate that NK activation by the aMQ is sufficient to generate the inflammatory requirements for lung fibrosis. Specific Aim 3: Ascertain the nature and molecular components of the aMQ-NK interface that results in the generation of a pro-fibrotic environment. This proposal is novel in that it will address the complex interactions between aMQ and NK within the context of the respiratory system using both in vitro and in vivo models. Upon completion of these studies, we expect to establish and test the relative contributions of specific subpopulations of macrophages and NK cells and determine those candidate molecules and signaling pathways by which these cells communicate leading to chronic inflammation and fibrosis. Furthermore, this body of work is anticipated to generate knowledge that will direct the development of novel therapeutic targets for the management of respiratory illnesses, including silica-induced inflammation and fibrosis. [unreadable] [unreadable] [unreadable]